Inhibitors of CACNA1A/ALPHA1A subunit internal ribosomal entry site (IRES) and methods of treating spinocerebellar ataxia type 6

Abstract

The invention provides methods of treating polyglutamine diseases, e.g., spinocerebellar ataxia Type 6, in a subject, comprising administering to the subject an IRES inhibitor in an amount effective for treating the SCA6 in the subject. Also provided herein are the IRES inhibitors, and pharmaceutical compositions comprising the same.

What is claimed is: 
     
       1. A method of treating spinocerebellar ataxia Type 6 (SCA6) in a subject in need thereof, comprising the step of administering to the subject (i) an antisense molecule, wherein the antisense molecule comprises the sequence of SEQ ID NO: 179, (ii) a vector encoding the antisense molecule, (iii) a cell comprising the vector or antisense molecule, (iv) an extracellular vesicle comprising the antisense molecule, or (v) a combination thereof, wherein the antisense molecule binds to a portion of an IRES of a CACNA1A gene comprising the sequence of SEQ ID NO: 180, optionally, wherein the antisense molecule binds to Argonaute 4 (Ago4). 
     
     
       2. The method of  claim 1 , wherein the vector comprises a nucleotide sequence encoding the miRNA comprising the sequence of SEQ ID NO: 179. 
     
     
       3. The method of  claim 2 , wherein the nucleotide sequence comprises of SEQ ID NO: 181. 
     
     
       4. The method of  claim 1 , wherein the antisense molecule is an antisense nucleic acid analog comprising the base sequence of SEQ ID NO: 179. 
     
     
       5. The method of  claim 1 , wherein the cell or extracellular vesicle is autologous to the subject. 
     
     
       6. A method of treating a subject with a predisposition to spinocerebellar ataxia Type 6 (SCA6), comprising the step of administering to the subject (i) an antisense molecule, wherein the antisense molecule comprises the sequence of SEQ ID NO: 179, (ii) a vector encoding the antisense molecule, (iii) a cell comprising the vector or antisense molecule, (iv) an extracellular vesicle comprising the antisense molecule, or (v) a combination thereof, wherein the antisense molecule binds to a portion of an IRES of a CACNA1A gene comprising the sequence of SEQ ID NO: 180, optionally, wherein the antisense molecule binds to Argonaute 4 (Ago4). 
     
     
       7. The method of  claim 6 , wherein the antisense molecule is a microRNA (miRNA), a pri-miRNA, or a pre-miRNA. 
     
     
       8. The method of  claim 6 , wherein the vector comprises a nucleotide sequence encoding the miRNA comprising the sequence of SEQ ID NO: 179. 
     
     
       9. The method of  claim 8 , wherein the nucleotide sequence comprises of SEQ ID NO: 181. 
     
     
       10. The method of  claim 6 , wherein the antisense molecule is an antisense nucleic acid analog comprising the base sequence of SEQ ID NO: 179. 
     
     
       11. The method of  claim 6 , wherein the cell or extracellular vesicle is autologous to the subject.